Project Summary: The ability to produce chiral, non-racemic compounds efficiently is central to both the medical chemistry and process chemistry aspects of pharmaceutical synthesis. While a substantial number of useful reactions now exist, many more are needed to more thoroughly access chemical space. The development of new reactions often requires significant empirical screening to achieve a desirable outcome in terms of both reaction yield and stereoisomeric purity. Therefore we are targeting, through a collaborative effort, a comprehensive approach to streamline catalyst optimization. We will address the essential question of how one might ?design? an asymmetric catalyst. Our proposed plan explores how catalyst and substrate structure interact to produce specific outcomes. Careful, classical mechanistic studies that reveal the fundamental mechanistic steps of reactions will be combined with modern physical organic parameterization/modeling techniques developed in the Sigman Group. The combination of these strategies will guide catalyst design and exploration of reaction scope. The field of asymmetric catalysis has come to recognize that the accumulation of weak, noncovalent interactions is critical in a myriad of enantioselective reactions. The unifying feature of the Aims of this project is a framework for understanding these forces as they culminate in efficient and highly selective catalysis. The elucidation of catalyst design strategies that can be adopted by the organometallic, organic and biological communities is our goal. In this context, the three Aims of the proposal evaluate three diverse modes of asymmetric catalysis. The first aim is focused on chiral anion catalysis where the non- covalent interactions responsible for asymmetric catalysis have been historically difficult to define due to the complexity of interrogating the substrate/catalyst contacts. We will exploit new technology developed in the Sigman group aided through previous collaborative studies between the Toste/Sigman and Miller/Sigman labs that allow mathematical relationships to be discovered, relating substrate and catalyst structure to physical organic measurements. This methodology not only allows for effective prediction, and thus the design of better performing catalysts, but also provides a contemporary, data-intensive approach to mechanistic study. In the second aim, we increase the complexity by evaluating organometallic reactions in combination with chiral anion catalysis (sometimes with two chiral elements) to develop a portfolio of new alkene difuntionalization reactions that have been initiated within both the Toste and Sigman labs. In the final aim, we ask questions pertaining to systems with greater dynamic aspects of both substrate and catalyst in the context of small peptide-catalyzed processes studied in the Miller lab. These efforts will test the limits of the modeling techniques as well as potentially impact the broad fields of directed evolution and enzyme catalyst design.